CN112979831B - Method for efficiently preparing raw material medicine icodextrin - Google Patents
Method for efficiently preparing raw material medicine icodextrin Download PDFInfo
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- CN112979831B CN112979831B CN202110409652.0A CN202110409652A CN112979831B CN 112979831 B CN112979831 B CN 112979831B CN 202110409652 A CN202110409652 A CN 202110409652A CN 112979831 B CN112979831 B CN 112979831B
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- C08B30/12—Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
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Abstract
A method for efficiently preparing raw material medicine icodextrin belongs to the technical field of medicine raw material preparation, and is characterized in that: sequentially comprises the following steps: gelatinization, acidolysis, decoloration and ultrafiltration process, which is characterized in that: the decoloring procedure is to adopt activated carbon and chitosan to decolor once or twice between pH value of 3-4; wherein the total adding amount of the activated carbon and the chitosan is 0.5-1g/L, and the adding amount of the chitosan is 0.05-0.1 time of the weight of the activated carbon. The invention optimizes the decoloring and ultrafiltration processes, adjusts the gelatinization and acidolysis processes, improves the reaction efficiency, increases the conversion rate, and has more concentrated molecular weight distribution of the target product.
Description
Technical Field
The invention relates to a method for efficiently preparing raw material medicine icodextrin, and belongs to the technical field of medicine raw material preparation.
Background
Icodextrin is used as the main active component of the peritoneal dialysis solution and is a water-soluble glucose polymer which is connected by alpha- (1-4) and less than 10 percent of alpha (1-6) glycosidic bond, the weight-average molecular weight is 13000-19000Da, and the number-average molecular weight is 5000-6500 Da.
Icodextrin peritoneal dialysis solution (Extraneal) manufactured by Baxter corporation has been approved for sale in Japan in 2003. Icodextrin as a glucose polymer can be degraded into a small molecular polymer through starch acidolysis, alkali liquor or enzymolysis, and then the icodextrin is obtained through molecular weight screening.
Chinese patent publication No. CN103467608A discloses icodextrin and a preparation method thereof, and the preparation method comprises the following steps: A. preparing grain starch and water into a solution with a substrate concentration of 20-50 wt%, adding an acid to form a reaction solution, wherein the final concentration of the acid is 0.1-1.5% (V/V), performing hydrolysis reaction at the temperature of 70-93 ℃, monitoring the reaction process, neutralizing the reaction solution to a pH of 7 with an alkali solution when the outflow time of the reaction solution is 2-4min measured by a Ubbelohde viscometer with the capillary diameter of 0.9-1.0mm, and stopping the hydrolysis reaction to obtain a product 1, wherein the reaction time is 0.5-4 h; B. screening the molecular weight of the product 1 to obtain a product 2 with the weight-average molecular weight of 1.3-1.9 ten thousand Da; C. and drying and curing the product 2 to obtain the product. The method of the application scheme is not purified, and the product has more impurities.
Chinese patent publication No. CN105524181A was treated by decoloring and fine filtering based on the above patent (CN103467608A), specifically by decoloring with activated carbon twice, fine filtering, and ultrafiltration, but no actual data supports specific product quality.
Chinese patent publication No. CN105131135A discloses an industrial production method of icodextrin, which comprises the following steps: a. preparing an acid solution with the concentration of 0.3-1.5%; b. taking 1000 parts by weight of acid solution, adding 400-450 parts by weight of corn starch while stirring, wherein the hydrolysis temperature is 90-95 ℃, and after hydrolysis reaction for 1-2 hours, adjusting the pH value to 5-7 to obtain a hydrolysis product; c. c, cooling the hydrolysate prepared in the step b to 55-60 ℃, adding 12-13.5 parts by weight of activated carbon, decoloring for 0.5-1 hour, and filtering after decoloring; d. and d, performing ultrafiltration and drying on the filtrate prepared in the step c to obtain the compound. The solution of this patent emphasizes the effect of discoloration on the color of the product feed and there is no explanation as to the degree of branching or molecular weight distribution of the product.
Chinese patent publication No. CN106755199A discloses a method for preparing icodextrin as a raw material of peritoneal dialysis solution, which comprises the following steps: (1) washing starch and then adding lysozyme for treatment; (2) after adopting debranching enzyme to hydrolyze, adding calcium chloride and alpha-amylase, and after hydrolysis treatment, adding acid to quickly inactivate the enzyme; (3) adding modified active carbon, and carrying out ultrasonic treatment; (4) screening the molecular weight of the hydrolysate in the filtrate C by using an ultrafiltration membrane; (5) and adding modified active carbon, filtering and drying after treatment to obtain the icodextrin. The invention has high preparation efficiency and yield, strong pertinence, convenient control of reaction depth, good consistency of hydrolyzed products and original ground products, and prevention of AGE generation, and can continuously carry out peritoneal dialysis. The technology of the patent is complex, the cost is high, and the technology is not suitable for industrial production.
Disclosure of Invention
The invention provides a method for efficiently preparing raw material medicine icodextrin, which optimizes decoloration and ultrafiltration processes, adjusts gelatinization and acidolysis processes, improves reaction efficiency, increases conversion rate, and has more concentrated molecular weight distribution of target products.
The invention specifically adopts the following technical scheme:
a method for efficiently preparing raw material medicine icodextrin sequentially comprises the following steps: starch gelatinization, acidolysis, decoloration and ultrafiltration process, which is characterized in that:
the decoloring procedure is to decolor once or twice by adopting activated carbon and chitosan at normal temperature between pH 3 and 4; wherein the total addition amount of the activated carbon and the chitosan is 0.5-1g/L, and the addition amount of the chitosan is 0.05-0.1 time of the weight of the activated carbon.
In the trial production, the applicant adopts 20-200nm and 2-5 μm activated carbon, under the condition that other parameters are not changed, the adsorption capacity of the activated carbon with the median particle size of 80nm, 200nm and 2.0 μm is found to be higher than that of the activated carbon with other particle sizes, and the activated carbon with the median particle size of 80nm or 200nm is preferably adopted in the invention in consideration of the difficulty of subsequently removing the activated carbon. In this case, the addition amount of the activated carbon is small compared with that of other particle sizes, so that the subsequent decolorization is convenient.
In addition, one of the inventive concepts of the present invention is that partially insoluble chitosan is added into activated carbon, and the applicant finds that trace proteins and salts in the decolorized solution interact with the activated carbon, so that the adsorption amount of the activated carbon is reduced, the activated carbon is sticky, and the subsequent filtration is difficult. The chitosan added in the invention can adsorb trace protein and salt, form flocculation and facilitate filtration.
The ultrafiltration adopts 100KDa and 5000Da ultrafiltration membranes to respectively carry out molecular weight screening; and (3) when a 5000Da ultrafiltration membrane is used for ultrafiltration, monitoring the value of the leachate to be between 0.2 and 0.5 by using a polarimeter, and stopping ultrafiltration.
Wherein the pressure of the ultrafiltration is 300-500KPa, and the applicant finds that the rejection rate is reduced obviously when the ultrafiltration pressure is more than 500KPa, and the pollution of the membrane is increased along with the increase of the pressure.
The gelatinization process comprises the steps of mixing and stirring starch and water at 90-100 ℃, and mixing the starch and the water at normal temperature, wherein the raw material is cereal or tuber plant starch; the addition amount of the insoluble organic particles is 1-2% of the weight of the starch.
Wherein the insoluble organic particles are polystyrene microspheres, insoluble cellulose particles or poly (N-isopropylacrylamide) microgel particles, and the most preferred is polystyrene microspheres, the maximum particle size of which is 25-50 nm, and the particle size uniformity of which is less than 3%.
The mechanism of adding the particle emulsifier in the pasting process is as follows:
the applicant carries out monitoring by adopting a rheometer and a differential scanning calorimeter in the starch gelatinization process of the invention, and finds that: 1) the endothermic peak during gelatinization is critical for the onset of starch gelatinization (in particular the time of appearance of the first endothermic peak), whereas the rheology during starch gelatinization has a correlation with the endothermic peak, in other words: the fluidity (or viscosity) of the starch paste is maintained in the gelatinization process, and the starch gelatinization in the gelatinization temperature rise process can be delayed or prevented; 2) the starch molecule fragment can be prevented from recombination between straight chain molecules and branched chain molecules and between branched chain molecules and branched chain molecules in the subsequent acidolysis process to a certain extent, so that the conversion rate of acidolysis is increased; 3) can increase gelatinizing dispersity and prevent insoluble particles.
In the present invention, the polystyrene microspheres are most preferable because the product is a mature commercial product.
The acidolysis process comprises the steps of controlling the temperature of the gelatinized starch to be a certain temperature, slowly dripping a prepared acid solution into the starch, slowly dripping the starch into a reaction solution, and keeping the temperature for reaction after dripping is finished.
Wherein the acid solution is hydrochloric acid, sulfuric acid or nitric acid solution, and the mass concentration of the acid solution is 0.2-0.5%;
wherein the acidolysis reaction temperature is 85-100 ℃, and the reaction time is 1-3 h.
Wherein the acid solution is added into the reaction solution step by step, and the dropwise adding time is controlled to be 30-50 min.
In the starch acidolysis process, the applicant finds that the swelling property of a reaction substrate and the correlation between the temperature rise speed and the acidolysis conversion rate are large, the insoluble organic particles added in the gelatinization process can reduce the swelling degree in the acidolysis process, and the temperature rise speed is reduced by adopting a dropwise adding mode, so that the acidolysis conversion rate can be effectively improved.
The invention also comprises the following steps:
compared with the prior art, the invention has the following beneficial effects:
1) according to the invention, before acidolysis, starch solution is gelatinized, and insoluble organic particles are added, so that starch is uniformly dispersed, starch aging is prevented, insoluble starch particles are reduced, and acidolysis conversion rate and yield are improved;
2) the decoloring process is optimized, and the decoloring efficiency and the adsorption capacity are improved; the ultrafiltration process is optimized, and the molecular weight screening is carried out more effectively;
3) the improvement of the acid adding mode enables the starch to be hydrolyzed more uniformly, and the molecular weight distribution index is within 2.5.
4) The acidolysis mode with low acid and high temperature is adopted, so that the generation of a large amount of subsequent salt is reduced, and the product quality is improved.
5) The external drainage liquid is tracked by a polarimeter in the 5000Da ultrafiltration process, and the process is stable and easy to control.
6) The reaction of the process is mild, and the alpha (1-6) glycosidic bond is less than 10 percent.
Drawings
FIG. 1 is an icodextrin nuclear magnetic carbon spectrum of the present invention;
FIG. 2 is a primary Extraneal nuclear magnetic carbon spectrum;
as can be seen from the comparison of FIGS. 1 and 2, the NMR spectrum of the final product is substantially the same as that of the original product Extraneal.
FIG. 3 is a molecular weight and distribution diagram of the product of the present invention.
Detailed Description
Example 1
1) Slurry mixing and liquefying: mixing 100g of starch, 300g of water and 1-2g of polystyrene microspheres at normal temperature, pulping, and stirring and gelatinizing in a 100 ℃ water bath kettle for 20 min;
2) cooling the gelatinized starch to 90 ℃, slowly dripping 100g of hydrochloric acid solution with the mass concentration of 0.27% into the reaction solution, and controlling the dripping within 30 min; keeping the temperature and reacting for 2 hours;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.3g of activated carbon and 0.015g of chitosan, decoloring at normal temperature, respectively using 100KDa and 5000Da ultrafiltration membranes to perform molecular weight screening, controlling the ultrafiltration pressure to be 300KPa, finishing ultrafiltration when the external drainage optical rotation value is tracked to be 0.200 by a polarimeter in the 5000Da ultrafiltration process, and performing spray drying on feed liquid to obtain a finished product. The yield is 67.4% (based on the dry product of the starch).
4) The icodextrin obtained in this example had a weight average molecular weight of 1.50 ten thousand Da, a number average molecular weight of 6300Da, and a distribution index of 2.38.
Example 2
1) Slurry mixing and liquefying: mixing starch 100g, water 800g and insoluble cellulose particles 1-2g at normal temperature, pulping, and stirring in 95 deg.C water bath for gelatinization for 30 min.
2) Controlling the gelatinized starch at 95 ℃, slowly dripping 100g of nitric acid solution with the mass concentration of 0.4% into the reaction solution within 40min, and finishing dripping; keeping the temperature and reacting for 3 hours;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.55g of activated carbon and 0.033g of chitosan, decoloring at normal temperature, respectively using 100KDa and 5000Da ultrafiltration membranes to perform molecular weight screening, finishing ultrafiltration when the ultrafiltration pressure is 300KPa and the ultrafiltration process of 5000Da is finished when the optical rotation value of the discharged liquid is 0.350 tracked by a polarimeter, and performing spray drying on feed liquid to obtain a finished product. The yield is 68.2 percent (based on dry starch).
4) The icodextrin obtained in this example had a weight average molecular weight of 1.41 ten thousand Da, a number average molecular weight of 6000Da, and a distribution index of 2.35
Example 3
1) Slurry mixing and liquefying: mixing 100g of starch, 200g of water and 1-2g of poly (N-isopropylacrylamide) microgel particles at normal temperature, pulping, and stirring and gelatinizing in a water bath kettle at 95 ℃ for 50 min;
2) reducing the gelatinized starch to 85 ℃, slowly dripping 100g of sulfuric acid solution with the mass concentration of 0.4% into the reaction solution, and controlling the dripping within 30 min; keeping the temperature and reacting for 2.5 h;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.36g of activated carbon and 0.025g of chitosan, decoloring at normal temperature, respectively using 100KDa and 5000Da ultrafiltration membranes to perform molecular weight screening, finishing ultrafiltration when the ultrafiltration pressure is 400KPa and the ultrafiltration value of the discharged liquor is 0.250 in 5000Da ultrafiltration process tracked by a polarimeter, and spray-drying the feed liquid to obtain the finished product. The yield is 67.7% (based on the dry starch).
4) The icodextrin obtained in this example had a weight average molecular weight of 1.58 ten thousand Da, a number average molecular weight of 6400Da, and a distribution index of 2.47.
Comparative example 1
1) Slurry mixing and liquefying: mixing starch 100g and water 300g at normal temperature, stirring and gelatinizing in a 100 deg.C water bath for 20 min;
2) reducing the gelatinized starch to 90 ℃, slowly dripping 100g of hydrochloric acid solution with the mass concentration of 0.27% into the reaction solution, and controlling the dripping within 30 min; keeping the temperature and reacting for 2 hours;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.3g of activated carbon and 0.015g of chitosan, decoloring at normal temperature, respectively using 100KDa and 5000Da ultrafiltration membranes to perform molecular weight screening, controlling the ultrafiltration pressure to be 300KPa, finishing ultrafiltration when the external drainage optical rotation value is tracked to be 0.200 by a polarimeter in the 5000Da ultrafiltration process, and performing spray drying on feed liquid to obtain a finished product. The yield is 53.1% (based on the dry product of the starch).
4) The icodextrin obtained in this example had a weight average molecular weight of 1.51 ten thousand Da, a number average molecular weight of 6000Da, and a distribution index of 2.52.
Comparative example 2
1) Size mixing: 100g of starch and 300g of water are mixed and blended at normal temperature, and then are placed in a water bath kettle with the temperature of 90 ℃.
2) Slowly dripping 100ml of hydrochloric acid solution with the mass concentration of 0.27%, and controlling the dripping within 30 min; keeping the temperature and reacting for 3 hours;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.36g of activated carbon and 0.025g of chitosan, decoloring at normal temperature, respectively using 100KDa and 5000Da ultrafiltration membranes to perform molecular weight screening, finishing ultrafiltration when the ultrafiltration pressure is 400KPa and the ultrafiltration value of the discharged liquor is 0.300 in 5000Da ultrafiltration process tracked by a polarimeter, and spray-drying the feed liquid to obtain the finished product. The yield is 49.7 percent (based on dry starch).
4) The icodextrin obtained in this example had a weight average molecular weight of 1.71 ten thousand Da, a number average molecular weight of 6000Da, and a distribution index of 2.85.
Comparative example 3
1) Slurry mixing and liquefying: mixing 100g of starch and 300g of water, pulping, adding sulfuric acid, and controlling the concentration of final acid to be 0.2%;
2) heating to 85 ℃, and reacting for 3.0 hours under the condition of heat preservation;
3) adjusting the pH value to 3-4, stopping the reaction, adding 0.36g of activated carbon and 0.025g of chitosan, decoloring at normal temperature, removing large molecular weight by using an ultrafiltration membrane of 100KDa, removing small molecular weight by using an ultrafiltration membrane of 5000Da, carrying out ultrafiltration at the ultrafiltration pressure of 400KPa, tracking the ultrafiltration effluent by a polarimeter until the optical rotation value is 0.400, finishing ultrafiltration, and carrying out spray drying on feed liquid to obtain a finished product. The yield thereof was found to be 46%.
4) The icodextrin obtained in this example had a weight average molecular weight of 1.74 ten thousand Da, a number average molecular weight of 5400Da, and a distribution index of 3.22.
Claims (6)
1. A method for efficiently preparing raw material medicine icodextrin sequentially comprises the following steps: starch gelatinization, acidolysis, decoloration and ultrafiltration process, which is characterized in that:
the gelatinization process comprises the steps of mixing and stirring starch, insoluble organic particles and water at 90-100 ℃, and pulping at normal temperature, wherein the insoluble organic particles are polystyrene microspheres, insoluble cellulose particles or poly (N-isopropylacrylamide) microgel particles, and the addition amount of the insoluble organic particles is 1-2% of the weight of the starch;
the acidolysis process comprises the steps of controlling the temperature of the gelatinized starch to be 85-100 ℃, and slowly dripping a prepared acid solution for reaction;
the decolorization process comprises the steps of decolorizing once or twice at normal temperature between pH (potential of hydrogen) and 3-4 by adopting activated carbon and chitosan; wherein the total adding amount of the activated carbon and the chitosan is 0.5-1g/L, and the adding amount of the chitosan is 0.05-0.1 time of the weight of the activated carbon;
the ultrafiltration process adopts 100KDa and 5000Da ultrafiltration membranes to respectively carry out molecular weight screening; by using
And (3) monitoring the value of the leachate to be between 0.2 and 0.5 by using a polarimeter when the 5000Da ultrafiltration membrane is subjected to ultrafiltration, and stopping ultrafiltration.
2. The method for efficiently preparing raw material icodextrin according to claim 1, characterized in that the raw material is derived from cereal or tuber plant starch.
3. The method for efficiently preparing raw material medicine icodextrin according to claim 1, characterized in that the activated carbon is activated carbon with a median particle size of 80nm or 200 nm.
4. The method for efficiently preparing raw material drug icodextrin according to claim 1, characterized in that the pressure of the ultrafiltration is 300-500 KPa.
5. The method for efficiently preparing raw material icodextrin according to claim 1, characterized in that the polystyrene microspheres have a maximum particle size of 25-50 nm and a particle size uniformity of less than 3%.
6. The method for efficiently preparing raw material medicine icodextrin according to claim 1, characterized in that the acid solution is hydrochloric acid, sulfuric acid or nitric acid solution, and the mass concentration of the acid solution is 0.2-0.5%.
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